Ophthalmic Device, and Method of Use Thereof, for Increasing Ocular Boundary Lubrication

ABSTRACT

The present invention provides an ophthalmic device, and method of use thereof, for an individual wearing an ophthalmic lens to increase ocular surface boundary lubrication. The invention device comprises an ophthalmic lens and a sacrificial mechanism disposed on the ophthalmic lens, wherein the sacrificial mechanism comprises a plurality of surface bound receptors, such as PRG4, hyaluronic acid, and DNA aptamers, that reversibly bound to a lubricating composition comprising a gel forming agent, a surfactant, or a combination thereof, effectively inhibiting or preventing protein and lipid adsorption on the surface of the lens, and mitigate shear stress and reduce the friction between the lens and the ocular surface of the individual in need.

CROSS-REFERENCE TO RELATED APPLICATIONS

This patent application is a continuation of PCT Application No.PCT/US09/043,018, filed May 6, 2009, which claims priority benefit ofU.S. Provisional Application No. 61/051,112 filed May 7, 2008, each ofwhich is incorporated herein by reference in their entireties.

FIELD OF THE INVENTION

The present invention relates to an ophthalmic device for the managementof ocular lubrication in the presence of an ophthalmic lens.

BACKGROUND

The proteoglycan 4 (prg4) gene encodes for highly glycosylated proteinstermed megakaryocyte stimulating factor (MSF), lubricin, and superficialzone protein (SZP) (1). These molecules are collectively referred to asPRG4 or PRG4 proteins. PRG4 is present in synovial fluid and at thesurface of synovium (2), tendon (3), and meniscus (4) and is suspectedas being an important component for healthy synovial joints. See, e.g.,(5), (6).

In tissues such as synovial joints, physicochemical modes of lubricationhave been classified as fluid film or boundary. The operativelubrication modes depend on the normal and tangential forces on thearticulating tissues, on the relative rate of tangential motion betweenthese surfaces, and on the time history of both loading and motion. Thefriction coefficient, provides a quantitative measure, and is defined asthe ratio of tangential friction force to the normal force. One type offluid-mediated lubrication mode is hydrostatic. At the onset of loadingand typically for a prolonged duration, the interstitial fluid withincartilage becomes pressurized, due to the biphasic nature of the tissue;fluid may also be forced into the asperities between articular surfacesthrough a weeping mechanism. Pressurized interstitial fluid and trappedlubricant pools may therefore contribute significantly to the bearing ofnormal load with little resistance to shear force, facilitating a verylow μ. Also, at the onset of loading and/or motion, squeeze film,hydrodynamic, and elastohydrodynamic types of fluid film lubricationoccur, with pressurization, motion, and deformation acting to driveviscous lubricant from and/or through the gap between two surfaces inrelative motion.

The relevant extent to which fluid pressure/film versus boundarylubrication occurs classically depends on a number of factors (13). Whenlubricant film can flow between the conforming sliding surfaces, whichcan deform elastically, elastohydrodynamic lubrication occurs. Pressure,surface roughness, and relative sliding velocity determine when fullfluid lubrication begins to break down and the lubrication enters newregimes. As velocity decreases further, lubricant films adherent to thearticulating surfaces begin to contribute and a mixed regime oflubrication occurs. If the velocity decreases even further and only anultra-thin lubricant layer composed of a few molecules remain, boundarylubrication occurs. A boundary mode of lubrication is thereforeindicated by a friction coefficient (ratio of the measured frictionalforce between two contacting surfaces in relative motion to the appliednormal force) during steady sliding being invariant with factors thatinfluence formation of a fluid film, such as relative sliding velocityand axial load (14). For articular cartilage, it has been concludedboundary lubrication is certain to occur, although complemented by fluidpressurization and other mechanisms (15-18).

In boundary lubrication, load is supported by surface-to-surfacecontact, and the associated frictional properties are determined bylubricant surface molecules. This mode has been proposed to be importantbecause the opposing cartilage layers make contact over ˜10% of thetotal area, and this may be where most of the friction occurs (19).Furthermore, with increasing loading time and dissipation of hydrostaticpressure, lubricant-coated surfaces bear an increasingly higher portionof the load relative to pressurized fluid, and consequently, this modecan become increasingly dominant (13, 20). Boundary lubrication, inessence, mitigates stick-slip (13), and is therefore manifest asdecreased resistance both to steady motion and the start-up of motion.The latter situation is relevant to load bearing articulating surfacesafter prolonged compressive loading (e.g., sitting or standing in vivo)(21). Typical wear patterns of cartilage surfaces (22) also suggest thatboundary lubrication of articular cartilage is critical to theprotection and maintenance of the articular surface structure.

With increasing loading time and dissipation of hydrostatic pressure,lubricant-coated surfaces bear an increasingly higher portion of theload relative to pressurized fluid, and consequently, μ can becomeincreasingly dominated by this mode of lubrication. A boundary mode oflubrication is indicated by values of μ during steady sliding beinginvariant with factors that influence formation of a fluid film, such asrelative sliding velocity and axial load. Boundary lubrication, inessence, mitigates stickslip, and is therefore manifest as decreasedresistance both to steady motion and the start-up of motion.

The precise mechanisms of boundary lubrication at biological interfacesare currently unknown. However, proteoglycan 4 (PRG4) may play acritical role as a boundary lubricant in articulating joints. Thissecreted glycoprotein is thought to protect cartilaginous surfacesagainst frictional forces, cell adhesion and protein deposition. Variousnative and recombinant lubricin proteins and isoforms have been isolatedand characterized. For instance, U.S. Pat. Nos. 5,326,558; 6,433,142;7,030,223, and 7,361,738 disclose a family of human megakaryocytestimulating factors (MSFs) and pharmaceutical compositions containingone or more such MSFs for treating disease states or disorders, such asa deficiency of platelets. U.S. Pat. Nos. 6,960,562 and 6,743,774 alsodisclose a lubricating polypeptide, tribonectin, comprising asubstantially pure fragments of MSF, and methods of lubricating jointsor other tissues by administering tribonectin systemically or directlyto tissues.

A challenge to boundary lubrication is the presence of inflammation insurrounding tissues, as well as increased protease levels in thesynovial fluid. Loss of the boundary-lubricating ability of synovialfluid after injury is associated with damage to the articular cartilagematrix. This can be attributed to inflammatory processes resulting fromthe injury, particularly in the early phases. Another challenge toboundary lubrication is a sex steroid imbalance, especially in arthriticdisorders such as rheumatoid arthritis. Sex steroids are involved in thepathogenesis and regulation of inflammation in rheumatoid arthritis, adisease characterized by chronic inflammatory synovitis. Androgenssuppress, whereas estrogens promote, inflammatory processes.Consequently, the relative levels of androgens and estrogens in thesynovial environment are extremely important in determining theprogression of inflammation (7, 8, 23). Various androgen compoundsreduce the magnitude of lymphocyte infiltration in lacrimal tissue. See,e.g., U.S. Pat. Nos. 5,620,921; 5,688,765; 5,620,921; and 6,107,289.

Engineering of contact lens surfaces have traditionally focused onincreasing oxygen transport. Recent advances in contact lens chemistrieshave also focused on increasing water content and hydrophilicity toinhibit protein deposition on the lens surface. Protein deposition onthe posterior/inner surface of the contact lens surfaces has beenimplicated as a causative factor in the corneal abrasions and mechanicaltrauma associated with contact lens wear.

loam Advances in silicone hydrogel materials have gained popularity dueto their ability to reduce protein absorption through increasedhydrophilicity. Examples include Lotrafilcon A (N,N-dimethylacrylamide,trimethylsiloxy silane and siloxane monomer, CIBA Vision, a.k.a. FocusNIGHT & DAY, 24% water content, 175 Dk/t O₂ transmissibility),Lotrafilcon B (N,N-dimethylacrylamide, trimethylsiloxy silane andsiloxane monomer, CIBA Vision, a.k.a. O₂ Optix, 33% water content, 138Dk/t O₂ transmissibility), Balafilcon (N-vinyl pyrrolidone,tris-(trimethylsiloxysilyl) propylvinyl carbamate, N-carboxyvinyl ester,poly(dimethysiloxy) di(silylbutanol) bis(vinyl carbamate), Bausch &Lomb, a.k.a. PureVision, 36% water content, 101 Dk/t O₂transmissibility), Galyfilcon A (monofunctional polydimethylsiloxane,dimethylacrylamide, poly-2-hydroxyethyl methacrylate, siloxane monomer,polyvinyl pyrrolidone, ethyleneglycol dimethacrylate, Johnson & JohnsonVision Care, a.k.a. ACUVUE Advance, 47% water content, 86 Dk/t O₂transmissibility), Etafilcon AA (poly-2-hydroxyethyl methacrylate,methacrylic acid, Johnson & Johnson Vision Care, a.k.a. ACUVUE 2, 58%water content, 21 Dk/t O₂ transmissibility). In addition to the materialchoices, these silicone hydrogel lenses are also manufactured with anadditional treatment steps to improve hydrophilicity. For example,Lotrafilcon A & B use plasma coating, Balafilcon A makes use of a plasmaoxidation process, and ACUVUE Advance lenses include polyvinylpyrrolidone as an internal wetting agent [25]. Plasma treatments areknown to fade and lose efficacy over time.

Protein adsorption at contact lens surfaces is commonly attributed tohuman albumin and lysozyme, two of the most abundant proteins in thetear film. Conflicting results have been reported regarding the watercontent, hydrophobicity, charge, pore size and surface roughness.Because the isoelectric points of albumin and lysozyme are on oppositeends of the pH of human tear, the minimum protein adsorption seems tooccur when charge, water content and hydrophilicity are properlybalanced. Lower water content materials tend to bind albumin whilehigher water content materials tend to bind lysozyme [24]. Luensmann et.al. [24] also indicated that silicone hydrogels exhibit both hydrophobicand hydrophilic domains; and following evaporation, chain rotationforces tend to expose hydrophobic domains to the air, thereby increasingthe chance for dry spots. Polar lipids may also bind to hydrophilicregions on the lens surface, resulting in exposed hydrophobic tails,which may also promote dry spots.

Hyperosmolarity is a common result of contact lens wear. Those with areduced quantity or quality of lipid production tend to exhibitdrastically less stable tear films, and the presence of a contact lensmay exacerbate the instability. This leads to a faster evaporation ofthe tear film, and a concentration of the tears over the ocular surface.

SUMMARY OF THE INVENTION

The present invention provides, in various embodiments, an ophthalmicdevice for the management of ocular lubrication in the presence of anophthalmic lens. Given the relationship between osmotic pressure and theelectromechanical interactions within charged molecules, the presentinvention provides for the methods of managing decreased ocular boundarylubrication in ophthalmic lens wear by modulating hyperosmolarity at theocular surface. In certain instances, by interrupting the feedbackmechanisms which promote hyperosmolarity, the integration of asacrificial mechanism into the pre- and/or postocular ophthalmic lensreduces the static and kinetic friction coefficient at the ocularsurface during an eyelid blink. In some instances, over time, thereduction in shear stress alleviates hyperosmolarity driven by the gainof this feedback mechanism.

Described in certain embodiments of the present invention is asacrificial mechanism disposed on at least a portion of the innersurface in an amount effective to provide ocular boundary lubrication inan individual wearing the ophthalmic lens. In one embodiment of thecurrent invention, the sacrificial mechanism comprises a plurality oflubricating surface bound receptors, such as plurality of PRG4 (i.e., aplurality of PRG4 molecules). In this embodiment, the lubricatingsurface bound receptor (e.g., PRG4) is allowed to interact withendogenous proteins and proteoglycans within the tear film to facilitateactivation of the sacrificial mechanism. In some instances, thisinteraction prevents or inhibits protein or lipid adsorption at the lenssurface, reduce dry spots on the lens, and reduce the friction betweenthe lens and the ocular surface. In preferred embodiments, the PRG4 hasan average molar mass of between 50 kDa and 400 kDa, and is recombinantPRG4, isolated naturally-occurring PGR4, or a functional fragmentthereof.

In some embodiments, the ophthalmic device of the current inventionfurther comprises a lubricating composition associated with or otherwisereversibly bound to surface active receptor(s) (e.g., PRG4) or surfaceof the opthalmic lens. In certain embodiments, the lubricatingcomposition described in the current invention comprises a gel formingagent or composition and/or a surfactant or surfactant composition, or acombination thereof. In one embodiment, the gel forming agent orcomposition comprises hyaluronic acid or sodium hyaluronate. In anotherembodiment, the surfactant or surfactant composition comprises one ormore surface active phospholids, such asL-α-dipalmitoylphosphatidylcholine, phosphatidylcholine,phosphatidylethanolamine, and sphingomyelin. Described in certainembodiments of the present invention is the observation that the gelforming or surfactant agent or composition associated with the boundarylubricant molecules detach during a shear event, thereby preventing theshear stress from reaching the epithelial surface. Following thetransient shearing event, the gel forming and/or surfactant agent orcomposition, allowed to return to their undisturbed equilibrium, rebindto the surface bound receptors and increase the probability of releasefrom the receptor with increasing shear amplitude, such that any oneassociation is easily reversible.

In further or alternative embodiments, the surface bound receptorscomprise hyaluronic acid. In this embodiment, the ophthalmic device ofthe current invention further comprises a lubricating agent orcomposition associated with, or otherwise reversibly bound to, thehyaluronic acid. The lubricating composition in this embodiment,comprises a gel forming composition comprising PRG4, and/or a surfactantcomposition comprising one or more surface active phospholipids, such asL-α-dipalmitoylphosphatidylcholine, phosphatidylcholine,phosphatidylethanolamine, and sphingomyelin.

In certain other embodiments, the surface bound receptors comprise DNAaptamers. DNA aptamers that may be utilized herein include those thatrecognize proteoglycans such as PRG4, hyaluronic acid, long chain sugarssuch as dextrans, polyethylene glycols, or other DNA constructs, andfeature tunable affinity through an iterative evolutionary selection, orthrough ratiometric design against a semi-complementary hybrid (i.e., apurposefully mismatched polyG-A-polyG could act as a surface boundreceptor for a polyG-T-polyG strand, with shortening lengths of polyGincreasing relative affinity).

In some embodiments, the sacrificial mechanism (e.g., comprising surfacebound receptor(s)) is bound to the ophthalmic lens by reversible and/orirreversible interactions (e.g., covalent bonds, non-covalentinteractions, or the like). In certain embodiments, the presentinvention provides that the surface bound receptors are adhered to theophthalmic lens surface by direct adsorption, hydrophobic ionic, orcovalent binding or by linker chemistries selected from the groupconsisting of homo- or hetero-bifunctional linkers, N-hydroxysuccinimidyl esters, biotin, avidin, streptavidin, maleimide, thiolbonding, amines, hydrazones, dendrimers, and carbodiimides.

Provided in certain embodiments herein is an ophthalmic devicecomprising an ophthalmic lens with an outer surface and an innersurface, PRG4, a PRG4 inducing compound, or a combination thereof beingassociated with at least a portion of the outer or inner surface in anamount effective to provide ocular boundary lubrication in an ocularenvironment of an individual wearing the ophthalmic lens. In someembodiments, the PRG4 is associated in a manner so as to provide asacrificial mechanism, as described herein. In certain embodiments, thePRG4 is bound to the surface of the ophthalmic lens. In someembodiments, a device described herein comprises a lubricatingcomposition disposed on the surface of the ophthalmic lens, thelubricating composition comprising (i) a gel-forming agent, asurfactant, or a combination thereof; and (ii) optionally PRG4.

In some embodiments, lubricating, gel forming or surfactant compositionfurther comprises one or more ophthalmically acceptable agents selectedfrom the group consisting of an ophthalmically acceptable demulcent,ophthalmically acceptable excipient, ophthalmically acceptableastringent, ophthalmically acceptable vasoconstrictor, andophthalmically acceptable emollient. Exemplary ophthalmically acceptabledemulcents contemplated in the present invention include, but are notlimited to, carboxymethylcellulose sodium (e.g., about 0.2 to 2.5% w/v),hydroxyethyl cellulose (e.g., about 0.2 to 2.5% w/v), hypromellose(e.g., about 0.2 to 2.5% w/v), methylcellulose (e.g., about 0.2 to 2.5%w/v), dextran 70 (e.g., about 0.1% w/v), gelatin (e.g., about 0.01%w/v), glycerin (e.g., about 0.2 to 1% w/v), polyethylene glycol 300(e.g., about 0.2 to 1% w/v), polyethylene glycol 400 (e.g., about 0.2 to1% w/v), polysorbate 80 (e.g., about 0.2 to 1% w/v), propylene glycol(e.g., about 0.2 to 1% w/v), polyvinyl alcohol (e.g., about 0.1 to 4%w/v), povidone (e.g., about 0.1 to 2% w/v).

Exemplary ophthalmically acceptable excipients/emollients contemplatedin the present invention include, but are not limited to, anhydrouslanolin (e.g., about 1 to 10% w/v), lanolin (e.g., about 1 to 10% w/v),light mineral oil (e.g., ≦about 50% w/v), mineral oil (e.g., ≦about 50%w/v), paraffin (e.g., ≦about 5% w/v), petrolatum (e.g., ≦about 100%w/v), white ointment (e.g., ≦about 100% w/v), white petrolatum (e.g.,≦about 100% w/v), white wax (e.g., ≦about 5% w/v), yellow wax (e.g.,≦about 5% w/v). An exemplary ophthalmically acceptable astringentcontemplated in the present invention includes, but is not limited, to,zinc sulfate (e.g., about 0.25% w/v). Exemplary ophthalmicallyacceptable vasoconstrictors contemplated in the present inventioninclude, but are not limited to, ephedrine hydrochloride (e.g., about0.123% w/v), naphazoline hydrochloride (e.g., about 0.01 to about 0.03%w/v), phenylephrine hydrochloride (e.g., about 0.08 to about 0.2% w/v),and tetrahydrozoline hydrochloride (e.g., about 0.01 to about 0.05%w/v).

In some of these embodiments, the demulcents, excipients, astringents,vasoconstrictors, emollients and electrolytes provide a means to deliverthe boundary lubricant molecules in an ophthalmically acceptable manner.Ophthalmically acceptable compositions are suitable for topicalapplication to the ocular surface if they lack unacceptable eyetoxicity, burning, itchiness, viscosity, blurred vision, etc. uponapplication.

In certain embodiments, the gel forming or surfactant compositionfurther comprises other ophthalmic lens care compounds that may besuspended in a phosphate buffered saline or an osmotically balanced saltsolution of tear electrolytes, including one or more of sodium chloride(e.g., about 44% to 54% mole fraction), potassium chloride (e.g., about8% to 14% mole fraction), sodium bicarbonate (e.g., about 8% to 18% molefraction), potassium bicarbonate (e.g., about 0% to 4% mole fraction),calcium chloride (e.g., about 0% to 4% mole fraction), magnesiumchloride (e.g., about 0% to 4% mole fraction), trisodium citrate (e.g.about 0% to 4% mole fraction), and hydrochloric acid (e.g., about 0% to20% mole fraction) or sodium hydroxide (e.g., about 0% to 20% molefraction). In one embodiment, the carrier could be formulated togenerate an aqueous electrolyte solution in the 150-200 mM range.

In certain embodiments, the ophthalmic lens care compounds are suspendedin an ophthalmically acceptable balanced salt solution comprising atleast three electrolytes, including but not limited to, sodium chloride(NaCl) 0.64%, potassium chloride (KCl) 0.075%, calcium chloridedihydrate (CaCl2.2H2O) 0.048%, magnesium chloride hexahydrate(MgCl2.6H2O) 0.03%, sodium acetate trihydrate (C2H3NaO2.3H2O) 0.39%,sodium citrate dehydrate (C6H5Na3O7.2H2O) 0.17%, sodium hydroxide and/orhydrochloric acid (to adjust pH to approximately 7.5) with an osmolarityof approximately 300 mOsms/L.

In certain embodiments, the ophthalmic lens Care compounds are suspendedin an ophthalmically acceptable balanced salt solution, comprised ofsodium (Na+) of approximately 128 mM, potassium (K+) of approximately 24mM, chloride (Cl−) of approximately 113 mM, calcium (Ca2+) ofapproximately 0.4 mM, magnesium (Mg2+) of approximately 0.3 mM, HCO3− ofapproximately 5 mM, citrate of approximately 1 mM, phosphate ofapproximately 14 mM, acetate of approximately 15 mM, and sodiumhydroxide and/or hydrochloric acid (to adjust pH to approximately 7.5)with an osmolarity of approximately 300 mOsms/L.

The present invention also provides an ophthalmic device comprising anophthalmic lens with an outer surface and an inner surface and an ocularboundary lubricant composition disposed on at least a portion thereofone or more ocular boundary lubricating agent, such as, by way ofnon-limiting example, of PRG4, a PGR4 inducer, hyaluronic acid, sodiumhyaluronate, and/or a phospholipid (e.g., in an amount effective toprovide, alone or in combination with the surface bound receptor, ocularboundary lubrication in an individual wearing the ophthalmic lens). Insome embodiments, a gel-forming or surfactant composition utilizedherein comprises, a gel forming agent and/or a surfactant, and anoptional ocular boundary lubricating agent, such as, by way ofnon-limiting example, PRG4, a PGR4 inducer, hyaluronic acid, sodiumhyaluronate, and/or a phospholipid (preferrably present in an amounteffective to provide, alone or in combination with the surface boundreceptor, ocular boundary lubrication in an individual wearing theophthalmic lens). Also provided in certain embodiments therein is amethod for providing ocular boundary lubrication to an individual inneed thereof by applying to an eye of the individual an ophthalmicdevice of the present invention. In some instances, the invention methodprovides a sacrificial mechanism on the ophthalmic lens to mitigateshear stress, so as to treat ocular surface hyperosmolarity.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 represents feedback loops within ocular surface boundarylubrication.

FIG. 2 illustrates PRG4 mRNA expression in human corneal epithelialcells. Human corneal epithelial cells were isolated from thecorneoscleral rims of male and female donors. Amplified samples werescreened for the presence of PRG4 products by using an Agilent 2100Bioanalyzer. Vertical lanes contain: L. MW ladder; 1. No templatecontrol; 2. Corneal tissue from a 33-year female; 4. Cultured cornealepithelial cells from a 70-year female; 6. Cultured corneal epithelialcells from a 53-year male.

FIG. 3 illustrates PRG4 mRNA expression in human conjunctival epithelialcells. Human corneal epithelial cells were isolated from thecorneoscleral rims of male and female donors. Amplified samples werescreened for the presence of PRG4 products by using agarose gelelectrophoresis. Vertical lanes contain: 1. MW ladder; 2. No templatecontrol; 4. Human female conjunctiva; 5. Human male conjunctiva.

FIG. 4 illustrates PRG4 mRNA expression in human corneoscleral rimtissue samples. L. Human corneal epithelial cells were isolated from thecorneoscleral rims of male and female donors. Amplified samples werescreened for the presence of PRG4 products by using an Agilent 2100Bioanalyzer. Vertical lanes contain: MW ladder; 1. Human liver cDNAstandard; 2. Corneoscleral rim tissue from a 24-year female; 3.Corneoscleral rim tissue from a 51-year female; 4. Human conjunctivalepithelial cells.

FIG. 5 illustrates PRG4 mRNA expression in human conjunctival impressioncytology samples. Conjunctival impression cytology samples were isolatedfrom male and female donors. Amplified samples were screened for thepresence of PRG4 products by using an Agilent 2100 Bioanalyzer. Verticallanes contain: L. MW ladder; 1-9. Conjunctival impression cytologysamples; 10. Repeat of human conjunctival epithelial cells (Lane 4 inFIG. 3).

FIG. 6 illustrates a friction test schematic. The corneal ocular surface(605) was fastened to the spherical end of an inert non-permeablesemi-rigid rubber plug cylinder (603) (radius r=6 mm). The plug cylinder(603) was attached to the rotational actuator of the mechanical testingmachine (Bose ELF 3200) forming the bottom articular surface. An annulus(601) (outer radius=3.2 mm, inner radius=1.5 mm) was punched from theeyelid (604). The annulus (601) was attached to the linear actuatorcoupled with an axial load (N) and torsion (t) load cells, forming theupper articulating surface. Lubricant bath (602) was formed by securingan inert tube around the plug cylinder (603). ω is the angularfrequency.

FIG. 7 illustrates the reduction of in vitro lid/cornea kinetic frictionwith addition of PRG4 protein (lubricin).

FIG. 8 illustrates the reduction of in vitro lid/cornea kinetic frictionmeasured 1 minute after the addition of PRG4 protein (lubricin).

FIG. 9 illustrates the reduction of in vitro lid/cornea kinetic frictionmeasured 5 minutes after the addition of PRG4 protein (lubricin).

FIG. 10 illustrates the reduction of in vitro lid/cornea kineticfriction over time, following addition of PRG4 protein (lubricin).

DETAILED DESCRIPTION OF THE INVENTION

Provided herein, are ophthalmic devices and methods for managing ocularboundary lubrication in association with ophthalmic lens wear. Incertain embodiments, the invention modulates hyperosmolarity at theocular surface via a sacrificial mechanism to improve ocular boundarylubrication. Provided herein is an ophthalmic device comprising anophthalmic lens with an outer surface and an inner surface and asacrificial mechanism disposed on at least a portion thereof in anamount effective to provide ocular boundary lubrication in an ocularenvironment in an individual wearing the ophthalmic lens.

Though not wishing to be bound by theoretical mechanisms of action, asshown in FIG. 1, increased shear stress leads to tear film instability,evaporative tear loss, hyperosmolarity, changes in swelling pressure anda feedback elevation in shear stress. In some instances, increased shearstress promotes inflammation, androgen deficiency and decreasedexpression of proteoglycans. In certain instances increased shear stressand its sequelae may, over time, lead to a loss of boundary lubricationat the ocular surface. A deficiency in ocular lubrication and symptomsassociated therewith can be determined by any suitable method. In someinstances, a deficiency in ocular lubrication and symptoms associatedtherewith is defined either qualitatively (e.g., a feeling of lowlubrication, dry eye, discomfort, etc.) or quantitatively (e.g.,measured through mechanical, biochemical, electrical, optical or othermethods of quantitative assays).

In certain instances, and as provided herein, PRG4 protein plays acritical role in the eye as a boundary lubricant. In some instances,this secreted glycoprotein protects the ocular surface to protect thecornea and conjunctiva against significant shear forces generated duringan eyelid blink, contact lens wear, and any other undesirable ocularboundary lubrication caused by chronic inflammation and hyperosmolaritythat result from dry eye disease, androgen deficiency, estrogenreplacement therapy, compromised tear film, allergy, aging, ocularsurface diseases, and increased protease levels in the tear film and atthe ocular surface. Given the relationship between osmotic pressure andthe electromechanical interactions within charged molecules, the presentinvention provides, in some embodiments, a pharmaceutical compositionfor managing a deficiency in ocular lubrication by modulatinghyperosmolarity or osmolarity at the ocular surface via interrupting thefeedback mechanisms that prevent secreted components from reducingfriction coefficients and mitigating shear stress.

The present invention features a sacrificial mechanism for ocularboundary lubrication in association with ophthalmic lens wear, wherebysurface bound receptors reversibly bind to a lubricating composition. Insome embodiments, the lubricating composition comprises one or more gelforming and/or surfactant agents or compositions. In some instances, thegel forming or surfactant composition detach during a shear event,thereby preventing the shear stress from reaching (or reducing the shearstress reaching), the epithelial surface. In certain embodiments,following the transient shearing event, the gel forming and surfactantcomposition, allowed to return to their undisturbed equilibrium, rebindto the surface bound receptors. In some embodiments, the entirecomposition can detach during shear. In certain instances, that thethermodynamics of this equilibrium increase the probability of releasefrom the receptor with increasing shear amplitude, but such that any oneassociation is easily reversible.

Therefore, the current invention generally features a new approach toocular lubrication in the presence of an ophthalmic lens. In particular,provided herein is a mechanism or process that relates to the use of asacrificial mechanism to reduce friction at the interface between theocular surface and an ophthalmic lens, including boundary lubricantmolecules such as PRG4, hyaluronic acid, sodium hyaluronate, andphospholipids.

As used herein, an “ophthalmic lens” refers to lenses which are placedin intimate contact with the eye or tear fluid, such as contact lensesfor vision correction (e.g., spherical, toric, bifocal), contact lensesfor modification of eye color, ophthalmic drug delivery devices, oculartissue protective devices (e.g., ophthalmic healing promoting lenses),and the like. A preferred ophthalmic lens is an extended-wear contactlens, especially extended-wear contact lenses for vision correction,with oxygen transmissibility or permeability, ion permeability, gaspermeability, and other desirable transmissibility or permeability andfeatures. As used herein, an “ocular environment” refers to ocularfluids (e.g., tear fluid) and ocular tissue (e.g., the cornea) which maycome into intimate contact with a contact lens used for visioncorrection, drug delivery, wound healing, eye color modification, orother ophthalmic applications.

As used herein, an “outer surface” of an ophthalmic lens refers to theanterior surface of the lens which faces away from the eye during wear.The outer surface, which is typically substantially convex, may also bereferred to as the front curve of the lens. The “inner surface” of alens, as used herein, refers to the posterior surface of the lens whichfaces towards the eye during wear. The inner surface, which is typicallysubstantially concave, may also be referred to as the base curve of thelens.

In one embodiment of the current invention, the sacrificial mechanismcomprises a plurality of surface bound receptor comprising PRG4, and alubricating composition reversibly bound to PRG4, wherein thelubricating composition comprises a gel forming composition comprisinghyaluronic acid or sodium hyaluronate, or a surfactant compositioncomprising one or more surface active phospholipids, such as,L-α-dipalmitoylphosphatidylcholine, phosphatidylcholine,phosphatidylethanolamine, and sphingomyelin. In this embodiment, PRG4 isallowed to interact with endogenous proteins and proteoglycans withinthe tear film, and the exogenously supplied hyaluronic acid and/orphospholipids to establish a sacrificial mechanism to prevent protein orlipid adsorption at the lens surface, reduce dry spots on the lens, andreduce the friction between the lens and the ocular surface. In yetanother feature of this embodiment, the hyaluronic acid and/orphospholipids are replenished in the form of a topical artificial teardrop, rewetting solution, contact lens cleaning products, an overnightincubation, or other contact lens care products.

As used herein, the terms “PRG4”, “PRG4 protein” or “proteoglycan 4” and“lubricin” are used interchangeably. PRG4 is used herein also toencompass the term megakaryocyte stimulating factor (MSF), that has beenaccepted for the UCL/HGNC/HUGO Human Gene Nomenclature data base, andsuperficial zone protein (SZP). The PRG4 or lubricin protein as usedherein refers to any isolated or purified native or recombinant lubricinproteins, homologs, functional fragments or motifs, isoforms, and/ormutants thereof. In certain embodiments, the isolated or purified PRG4protein comprises an amino acid sequence for a human native orrecombinant lubricin protein. In other embodiments, the isolated orpurified PRG4 protein comprises an amino acid sequence encoded byprg4gene exons that encode the full length PRG4 protein or isoforms'primary structures. The proteoglycan 4 (prg4) gene contains 12 exons.The PRG4 protein used herein can comprise an amino acid sequence encodedby prg4gene exons 1-12, more preferably, exons 6-12, and mostpreferably, exons 9-12.

As used herein, the PRG4 protein includes any PRG4 proteins now known,or later described. In certain embodiments, a preferred PRG4 proteinamino acid sequence is provided in SEQ ID NO: 1. The PRG4 protein sharesthe primary amino acid structure of any known PRG4 proteins or isoformswith at least 60% homology, preferably 75% homology, more preferably85%, 90%, 95%, 96%, 97%, 98%, 99% or more homology. In certainembodiments, a preferred PRG4 protein has an average molar mass ofbetween 50 kDa and 400 kDa, comprising one or more biological activeportions of the PRG4 protein, or functional fragments, such as alubricating fragment, or a homolog thereof.

In yet another embodiment, functional fragments, multimers (e.g.,dimers, trimers, tetramers, etc.), homologs or orthologs of PRG4 act asthe surface receptor and/or gel forming constructs in the sacrificialmechanism. Functional fragments and homologs of PRG4 include those witha fewer repeats within the central mucin-like KEPAPTT-repeat domain,glycosylated and non-glycosylated forms of the protein, splice variants,recombinant forms, and the like. A lubricating fragment of PRG4 exhibitsat least 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 95% of theophthalmic lubricating effect of human PRG4, as measured qualitatively,mechanically, optically, electrically, or by biochemical assay.

As used herein, the PRG4 protein comprises a biological active portionof the protein. As used herein, a “biologically active portion” of thePRG4 protein includes a functional fragment of a protein comprisingamino acid sequences sufficiently homologous to, or derived from, theamino acid sequence of the protein, which includes fewer amino acidsthan the full length protein, and exhibits at least one activity of thefull-length protein. Typically a biologically active portion comprises afunctional domain or motif with at least one activity of the protein. Abiologically active portion of a protein can be a polypeptide which is,for example, 10, 25, 50, 100, 200, or more amino acids in length. In oneembodiment, a biologically active portion of the PRG4 protein can beused as a therapeutic agent alone or in combination with othertherapeutic agents for treating undesirable or decreased ocular boundarylubrication.

The nucleic acid and amino acid sequences of several native andrecombinant PRG4 or lubricin proteins, and characterization of the PRG4proteins and various isoforms are disclosed in, for instance, U.S. Pat.Nos. 5,326,558; 6,433,142; 7,030,223; 7,361,738 to Turner et al., andU.S. Pat. Nos. 6,743,774 and 6,960,562 to Jay et al. U.S. PublicationNo. 20070191268 to Flannery et al. also discloses recombinant PRG4 orlubricin molecules useful in the present invention.

Methods for isolation, purification, and recombinant expression of aPRG4 protein are well known in the art. In certain embodiments, themethod starts with cloning and isolating mRNA and cDNA encoding PRG4proteins or isoforms using standard molecular biology techniques, suchas PCR or RT-PCR. The isolated cDNA encoding the PRG4 protein or isoformis then cloned into an expression vector, and further transformed andexpressed in a host cell for producing recombinant PRG4 protein.

As used herein, “recombinant” refers to a polynucleotide synthesized orotherwise manipulated in vitro (e.g., “recombinant polynucleotide”), tomethods of using recombinant polynucleotides to produce gene products incells or other biological systems, or to a polypeptide (“recombinantprotein”) encoded by a recombinant polynucleotide. “Recombinant” alsoencompasses the ligation of nucleic acids having various coding regionsor domains or promoter sequences from different sources into anexpression cassette or vector for expression of, e.g., inducible orconstitutive expression of a fusion protein comprising an active domainof the PRG4 gene and a nucleic acid sequence amplified using a primer ofthe invention.

In certain embodiments, the PRG4 protein encoding nucleic acid maycontain one or more mutations, deletions, or insertions. In suchembodiments, the PRG4 protein encoding nucleic acid is at least 60%homology, preferably 75% homology, more preferably 85%, 90%, 95%, 96%,97%, 98%, 99%, or more homology, to a wild type PRG4 protein encodingnucleic acid.

As used herein, the term ‘cDNAs” includes DNA that is complementary tomRNA molecules present in a cell or organism mRNA that can be convenedinto cDNA with an enzyme such as reverse transcriptase. In certainembodiments, the cDNA encoding PRG4 protein is isolated from PRG4 mRNAexpressed in human corneal or conjunctival epithelial cells using anRT-PCR method well known in the art.

As used herein, the terms “polynucleotide,” “nucleic acid/nucleotide,”and “oligonucleotide” are used interchangeably, and include polymericforms of nucleotides of any length, either deoxyribonucleotides orribonucleotides, or analogs thereof. Polynucleotides may have anythree-dimensional structure, and may perform any function, known orunknown. The following are non-limiting examples of polynucleotides: agene or gene fragment, exons, introns, messenger RNA (mRNA), transferRNA, ribosomal RNA, ribozymes, DNA, cDNA, genomic DNA, recombinantpolynucleotides, branched polynucleotides, plasmids, vectors, isolatedDNA of any sequence, isolated RNA of any sequence, nucleic acid probes,and primers. Polynucleotides may be naturally-occurring, synthetic,recombinant or any combination thereof.

A polynucleotide may comprise modified nucleotides, such as methylatednucleotides and nucleotide analogs. If present, modifications to thenucleotide structure may be imparted before or after assembly of thepolymer. The sequence of nucleotides may be interrupted bynon-nucleotide components. A polynucleotide may be further modifiedafter polymerization, such as by conjugation with a labeling component.The term also includes both double- and single-stranded molecules.Unless otherwise specified or required, any embodiment of this inventionthat is a polynucleotide encompasses both the double-stranded form andeach of two complementary single-stranded forms known or predicted tomake up the double-stranded form.

As used herein, the term “polynucleotide sequence” is the alphabeticalrepresentation of a polynucleotide molecule. A polynucleotide iscomposed of a specific sequence of four nucleotide bases: adenine (A);cytosine (C); guanine (G); thymine (T); and uracil (U) in place ofthymine when the polynucleotide is RNA, instead of DNA. Thisalphabetical representation can be inputted into databases in a computerand used for bioinformatics applications such as, for example,functional genomics and homology searching.

As used herein, the term “isolated polynucleotide/cDNA” includespolynucleotide molecules which are separated from other polynucleotidemolecules which are present in the natural source of the polynucleotide.For example, with regard to genomic DNA, the term “isolated” includespolynucleotide molecules which are separated from the chromosome withwhich the genomic DNA is naturally associated. Preferably, an “isolated”polynucleotide is free of sequences which naturally flank thepolynucleotide (i.e., sequences located at the 5′ and 3′ ends of thepolynucleotide of interest) in the genomic DNA of the organism fromwhich the polynucleotide is derived. For example, in variousembodiments, the isolated polynucleotide molecule encoding the PRG4protein used in the invention can contain less than about 5 kb, 4 kb, 3kb, 2 kb, 1 kb, 0.5 kb or 0.1 kb of nucleotide sequences which naturallyflank the polynucleotide molecule in genomic DNA of the cell from whichthe polynucleotide is derived. Moreover, an “isolated” polynucleotidemolecule, such as a cDNA molecule, can be substantially free of othercellular material, or culture medium when produced by recombinanttechniques, or substantially free of chemical precursors or otherchemicals when chemically synthesized.

As used herein, a “gene” includes a polynucleotide containing at leastone open reading frame that is capable of encoding a particularpolypeptide or protein after being transcribed and translated. Any ofthe polynucleotide sequences described herein may also be used toidentify larger fragments or full-length coding sequences of the genewith which they are associated. Methods of isolating larger fragmentsequences are known to those of skill in the art. As used herein, a“native or naturally-occurring” polynucleotide molecule includes, forexample, an RNA or DNA molecule having a nucleotide sequence that occursin nature (e.g., encodes a natural protein).

As used herein, the term “polypeptide” or “protein” is interchangeable,and includes a compound of two or more subunit amino acids, amino acidanalogs, or peptidomimetics. The subunits may be linked by peptidebonds. In another embodiment, the subunit may be linked by other bonds,e.g., ester, ether, etc. As used herein, the term “amino acid” includeseither natural and/or unnatural or synthetic amino acids, includingglycine and both the D or L optical isomers, and amino acid analogs andpeptidomimetics. A peptide of three or more amino acids is commonlyreferred to as an oligopeptide. Peptide chains of greater than three ormore amino acids are referred to as a polypeptide or a protein.

In certain embodiments, the PRG4 protein used herein refers to PRG4proteins or various homologs or isoforms thereof, that are naturally orrecombinantly expressed in humans or other host cells. As used herein,“express” or “expression” includes the process by which polynucleotidesare transcribed into RNA and/or translated into polypeptides. If thepolynucleotide is derived from genomic DNA, expression may includesplicing of the RNA, if an appropriate eukaryotic host is selected.Regulatory elements required for expression include promoter sequencesto bind RNA polymerase and transcription initiation sequences forribosome binding. For example, a bacterial expression vector includes apromoter such as the lac promoter and for transcription initiation theShine-Dalgarno sequence and the start codon AUG. Similarly, a eukaryoticexpression vector includes a heterologous or homologous promoter for RNApolymerase II, a downstream polyadenylation signal, the start codon AUG,and a termination codon for detachment of the ribosome. Such vectors canbe obtained commercially or assembled by the sequences described inmethods well known in the art, for example, the methods described belowfor constructing vectors in general. As used herein, the term “vector”includes a self-replicating nucleic acid molecule that transfers aninserted polynucleotide into and/or between host cells. The term isintended to include vectors that function primarily for insertion of anucleic acid molecule into a cell, replication vectors that functionprimarily for the replication of nucleic acid and expression vectorsthat function for transcription and/or translation of the DNA or RNA.Also intended are vectors that provide more than one of the abovefunction.

As used herein, a “host cell” is intended to include any individual cellor cell culture which can be, or has been, a recipient for vectors orfor the incorporation of exogenous polynucleotides and/or polypeptides.It is also intended to include progeny of a single cell. The progeny maynot necessarily be completely identical (in morphology or in genomic ortotal DNA complement) to the original parent cell due to natural,accidental, or deliberate mutation. The cells may be prokaryotic oreukaryotic, and include but are not limited to bacterial cells, yeastcells, insect cells, animal cells, and mammalian cells, including butnot limited to murine, rat, simian or human cells. As used herein, a“host cell” also includes genetically modified cells. The term“genetically modified cells” includes cells containing and/or expressinga foreign or exogenous gene or polynucleotide sequence which in turnmodifies the genotype or phenotype of the cell or its progeny.“Genetically modified” also includes a cell containing or expressing agene or polynucleotide sequence which has been introduced into the cell.For example, in this embodiment, a genetically modified cell has hadintroduced a gene which gene is also endogenous to the cell. The term“genetically modified” also includes any addition, deletion, ordisruption to a cell's endogenous nucleotides. As used herein, a “hostcell” can be any cells that express a human PRG4 protein.

As used herein, “homologs” are defined herein as two nucleic acids orpeptides that have similar, or substantially identical, nucleic acids oramino acid sequences, respectively. The term “homolog” furtherencompasses nucleic acid molecules that differ from one of thenucleotide sequences due to degeneracy of the genetic code and thusencodes the same amino acid sequences. In one of the preferredembodiments, homologs include allelic variants, orthologs, paralogs,agonists, and antagonists of nucleic acids encoding the PRG4 protein(e.g., SEQ ID NO:1).

As used herein, the term “orthologs” refers to two nucleic acids fromdifferent species, but that have evolved from a common ancestral gene byspeciation. Normally, orthologs encode peptides having the same orsimilar functions. In particular, orthologs of the invention willgenerally exhibit at least 80-85%, more preferably 85-90% or 90-95%, andmost preferably 95%, 96%, 97%, 98%, or even 99% identity, or 100%sequence identity, with all or part of the amino acid sequence of anyknown PRG4 proteins (e.g., SEQ ID NO:1), isoforms, or analogs thereof,and will exhibit a function similar to these peptides. As also Usedherein, the term “paralogs” refers to two nucleic acids that are relatedby duplication within a genome. Paralogs usually have differentfunctions, but these functions may be related.

To determine the percent sequence identity of two amino acid sequences,the sequences are aligned for optimal comparison purposes (e.g., gapscan be introduced in the sequence of one polypeptide for optimalalignment with the other polypeptide or nucleic acid). The amino acidresidues at corresponding amino acid positions are then compared. When aposition in one sequence is occupied by the same amino acid residue asthe corresponding position in the other sequence, then the molecules areidentical at that position. The same type of comparison can be madebetween two nucleic acid sequences. The percent sequence identitybetween the two sequences is a function of the number of identicalpositions shared by the sequences (i.e., percent sequenceidentity=numbers of identical positions/total numbers of positions×100).Preferably, the isolated amino acid homologs included in the presentinvention are at least about 50-60%, preferably at least about 60-70%,and more preferably at least about 70-75%, 75-80%, 80-85%, 85-90%, or90-95%, and most preferably at least about 96%, 97%, 98%, 99%, or moreidentical to an entire amino acid sequence of any known PRG4 protein(e.g., SEQ ID NO:1).

In certain embodiments, an isolated nucleic acid homolog encoding thePRG4 protein comprises a nucleotide sequence which is at least about40-60%, preferably at least about 60-70%, more preferably at least about70-75%, 75-80%, 80-85%, 85-90%, or 90-95%, and even more preferably atleast about 95%, 96%, 97%, 98%, 99%, or more identical to a nucleotidesequence encoding amino acid sequences of such PRG4 protein (e.g., SEQID NO: 1).

The determination of the percent sequence identity between two nucleicacid or peptide sequences is well known in the art. For instance, theVector NTI 6.0 (PC) software package (InforMax, Bethesda, Md.) todetermine the percent sequence identity between two nucleic acid orpeptide sequences can be used. In this method, a gap opening penalty of15 and a gap extension penalty of 6.66 are used for determining thepercent identity of two nucleic acids. A gap opening penalty of 10 and agap extension penalty of 0.1 are used for determining the percentidentity of two polypeptides. All other parameters are set at thedefault settings. For purposes of a multiple alignment (Clustal Walgorithm), the gap opening penalty is 10, and the gap extension penaltyis 0.05 with blosum62 matrix. It is to be understood that for thepurposes of determining sequence identity when comparing a DNA sequenceto an RNA sequence, a thymidine nucleotide is equivalent to a uracilnucleotide.

Furthermore, the PRG4 protein used herein includes PRG4 protein encodedby a polynucleotide that hybridizes to the polynucleotide encoding PRG4protein under stringent conditions. As used herein, “hybridization”includes a reaction in which one or more polynucleotides react to form acomplex that is stabilized via hydrogen bonding between the bases of thenucleotide residues. The hydrogen bonding may occur by Watson-Crick basepairing, Hoogstein binding, or in any other sequence-specific manner.The complex may comprise two strands forming a duplex structure, threeor more strands forming a multi-stranded complex, a singleself-hybridizing strand, or any combination of these. A hybridizationreaction may constitute a step in a more extensive process, such as theinitiation of a PCR reaction, or the enzymatic cleavage of apolynucleotide by a ribozymc.

Hybridization reactions can be performed under different stringentconditions. The present invention includes polynucleotides capable ofhybridizing under reduced stringency conditions, more preferablystringent conditions, and most preferably highly stringent conditions,to polynucleotides encoding PRG4 protein described herein. As usedherein, the term “stringent conditions” refers to hybridizationovernight at 60° C. in 10×Denhart's solution, 6×SSC, 0.5% SDS, and 100mg/ml denatured salmon sperm DNA. Blots are washed sequentially at 62°C. for 30 minutes each time in 3×SSC/0.1% SDS, followed by 1×SSC/0.1%SDS, and finally 0.1×SSC/0.1% SDS. As also used herein, in certainembodiments, the phrase “stringent conditions” refers to hybridizationin a 6×SSC solution at 65° C. In other embodiments, “highly stringentconditions” refer to hybridization overnight at 65° C. in 10×Denhart'ssolution, 6×SSC, 0.5% SDS and 100 mg/ml denatured salmon sperm DNΔ.Blots are washed sequentially at 65° C. for 30 minutes each time in3×SSC/0.1% SDS, followed by 1×SSC/0.1% SDS, and finally 0.1×SSC/0.1%SDS. Methods for nucleic acid hybridizations are well known in the art.Accordingly, the PRG4 proteins encoded by nucleic acids used hereininclude nucleic acid having at least 60% homology, preferably 75%homology, more preferably 85%, more preferably 90%, most preferably 95%,96%, 97%, 98%, 99% homology to a polynucleotide sequence that encodes ahuman PRG4 protein (e.g., SEQ ID NO:1) or a specific isoform or homologthereof.

Moreover, the PRG4 proteins used herein can also be chimeric protein orfusion protein. As used herein, a “chimeric protein” or “fusion protein”comprises a first polypeptide operatively linked to a secondpolypeptide. Chimeric proteins may optionally comprise a third, fourthor fifth or other polypeptide operatively linked to a first or secondpolypeptide. Chimeric proteins may comprise two or more differentpolypeptides. Chimeric proteins may comprise multiple copies of the samepolypeptide. Chimeric proteins may also comprise one or more mutationsin one or more of the polypeptides. Methods for making chimeric proteinsare well known in the art. In certain embodiments of the presentinvention, the chimeric protein is a chimera of PRG4 protein with otherPRG4 protein isoforms.

As used herein, an “isolated” or “purified” protein, polynucleotide ormolecule means removed from the environment in which they naturallyoccur, or substantially free of cellular material, such as othercontaminating proteins from the cell or tissue source from which theprotein polynucleotide or molecule is derived, or substantially freefrom chemical precursors or other chemicals when chemically synthesized.The language “substantially free of cellular material” includespreparations separated from cellular components of the cells from whichit is isolated or recombinantly produced or synthesized. In certainembodiments, the language “substantially free of cellular material”includes preparations of a PRG4 protein having less than about 30% (bydry weight) of other proteins (also referred to herein as a“contaminating protein”), more preferably less than about 20%, stillmore preferably less than about 10%, and most preferably less than about5% of other proteins. When the protein or polynucleotide isrecombinantly produced, it is also preferably substantially free ofculture medium, i.e., culture medium represents less than about 20%,more preferably less than about 10%, and most preferably less than about5% of the volume of the preparation of the protein of interest.

In certain embodiments of the current invention, the surface boundreceptors comprise hyaluronic acid. In this embodiment, the lubricatingcomposition reversibly bound to the hyaluronic acid, wherein thelubricating composition comprises a gel forming composition comprisingPRG4 and a surfactant composition comprising one or more surface activephospholipids, including but not limited to,L-α-dipalmitoylphosphatidylcholine, phosphatidylcholine,phosphatidylethanolamine, and sphingomyelin.

The present invention also provides an ophthalmic device comprising anophthalmic lens with an outer surface and a inner surface and an ocularboundary lubricant composition disposed on at least a portion thereofone or more ocular boundary lubricant molecules selected from the groupconsisting of PRG4, a PGR4 inducer, hyaluronic acid, sodium hyaluronate,and a phospholipid, in an amount effective to provide ocular boundarylubrication in a patient wearing the ophthalmic lens.

As used herein, a “PRG4 inducing compound” or “PRG4 inducer” refers to acompound that increases the bioconcentration of PRG4, e.g., a compoundthat is capable of upregulating PRG4 expression, promoting thebiosynthesis of PRG4, inhibiting degradation of PRG4, or the like,including but not limited to, an androgen or androgen analogue,selective androgen receptor modulator, selective estrogen receptormodulator, estrogen antagonist, aromatase inhibitor, antiprotease,proinflammatory cytokine antagonist (e.g. selected from the groupconsisting of anti-TNFα antibody, soluble TNFα receptor, and IL-1receptor antagonist), cytokine release inhibitor, antiinflammatorycytokine (e.g. TGF-β), antiinflammatory agent (e.g. cyclosporine A,omega 3 and 6 fatty acids), NF-κ B inhibitor, or proteasome inhibitor,and pharmaceutically acceptable carriers for topical use.

In yet another embodiment, the androgen or androgen analogue is selectedfrom the group consisting of a17α-methyl-17β-hydroxy-2-oxa-5α-androstan-3-one derivative, anitrogen-substituted androgen, a testosterone derivative, is a4,5α-dihydrotestosterone derivative, a 19-nortestosterone derivative, a17β-hydroxy-5α-androstane derivative containing a ring A unsaturation,and a structural subclass of androgens comprising androgenic compoundswith unusual structural features.

In another preferred embodiment, the selective androgen receptormodulators (SARMs) are selected from a group consisting ofaryl-propionamide (e.g.S-3-(4-acetylamino-phenoxy)-2-hydroxy-2-methyl-N-(4-nitro-3-trifluoromethyl-phenyl)-propionamide[S-4], orS-3-(4-fluorophenoxy)-2-hydroxy-2-methyl-N-(4-nitro-3-trifluoromethyl-phenyl)-propionamide[S-1]), bicyclic hydantoin, quinoline, and tetrahydroquinoline analoguesthat have in-vivo androgenic and anabolic activity of a non-steroidalligand for the androgen receptor.

In yet another preferred embodiment, the selective estrogen receptormodulators (SERMs) are non-steroidal ligands of the estrogen receptorthat are capable of inducing a number of conformational changes in thereceptor and eliciting a variety of distinct biologic profiles.Preferably, the SERMs are those that prevent estrogen-inducedinflammation in ocular surface tissues. In certain preferredembodiments, the estrogen antagonists are steroidal or non-steroidalcompounds independent of receptor affinities.

Other molecules may also be used as surface bound receptors within thesacrificial mechanism of the current invention. For instance, DNAsequences recognizing gel forming or surfactant compositions (e.g., DNAaptamers), would serve as the surface bound receptor. These aptamerscould recognize proteoglycans such as PRG4, hyaluronic acid, long chainsugars such as dextrans, polyethylene glycols, or other DNA constructs.The surface bound DNA could feature tunable affinity through aniterative evolutionary selection, or through ratiometric design againsta semi-complementary hybrid (i.e., a purposefully mismatchedpolyG-A-polyG could act as a surface bound receptor for a polyG-T-polyGstrand, with shortening lengths of polyG increasing relative affinity).

In certain embodiments, the surface bound receptors are adhered to theophthalmic lens surface by direct adsorption, hydrophobic ionic, orcovalent binding or by linker chemistries selected from the groupconsisting of homo- or hetero-bifunctional linkers, N-hydroxysuccinimidyl esters, biotin, avidin, streptavidin, maleimide, thiolbonding, amines, hydrazones, dendrimers, and carbodiimides. Methods fordisposing, adhering, coating, or attaching the surface bound receptors,or other desirable molecules, chemistries, monomers, oligomers, andpolymers, to the ophthalmic lens are well known in the art.

In certain embodiments, the present invention provides that the gelforming or surfactant composition of the current invention furthercomprises one or more therapeutically effective amount or concentrationof ophthalmically compatible and/or acceptable agents selected from thegroup consisting of an ophthalmically acceptable demulcent, excipient,astringent, vasoconstrictor, and emollient. As used herein, the term“ophthalmically compatible” refers to a material or surface of amaterial which may be in intimate contact with the ocular environmentfor an extended period of time without significantly damaging the ocularenvironment and without significant user discomfort. Thus, anophthalmically compatible contact lens will not produce significantcorneal swelling, will adequately move on the eye with blinking topromote adequate tear exchange, will not have substantial amounts oflipid adsorption, and will not cause substantial wearer discomfortduring the prescribed period of wear.

As used herein, the term “effective concentration or amount” or“therapeutically effective concentration or amount” is intended to meana nontoxic but sufficient concentration or amount to provide the desiredtherapeutic effects. The concentration or amount that is effective willvary from subject to subject, depending on the age and general conditionof the individual, the particular agents, and the like. Thus, it is notalways possible to specify an exact effective concentration or amount.However, an appropriate effective concentration or amount in anyindividual case may be determined by one of ordinary skill in the artusing routine experimentation. Furthermore, the exact effectiveconcentration or amount of the boundary lubricant molecules used hereinand other therapeutic agent incorporated thereinto or dosage form of thepresent invention is not critical, so long as the concentration iswithin a range sufficient to permit ready application of the solution orformulation so as to deliver an amount of the boundary lubricantmolecules and other active agents that is within a therapeuticallyeffective range.

In certain embodiments, the pharmaceutically effective concentration ofPRG4 protein is in a range of 10-10,000 μg/mL, preferably 50-5,00 mg/mL,and more preferably 100-300 mg/mL. As used herein, the ophthalmicallyacceptable agents comprising the ophthalmically acceptable demulcents,excipients, astringents, vasoconstrictors, and emollients that are fullydefined in the Code of Federal Regulations 21CFR349.

In certain embodiments, the lubricating composition described hereincomprises or the aforementioned ophthalmically acceptable agents are orcan be combined with one or more of carboxymethylcellulose sodium (e.g.,about 0.2 to about 2.5% w/v), hydroxyethyl cellulose (e.g., about 0.2 toabout 2.5% w/v), hypromellose (e.g., about 0.2 to about 2.5% w/v),methylcellulose (e.g., about 0.2 to about 2.5% w/v), dextran 70 (e.g.,about 0.1% w/v), gelatin (e.g., about 0.01% w/v), glycerin (e.g., about0.2 to about 1% w/v), polyethylene glycol 300 (e.g., about 0.2 to about1% w/v), polyethylene glycol 400 (e.g., about 0.2 to about 1% w/v),polysorbate 80 (e.g., about 0.2 to about 1% w/v), propylene glycol.(e.g., about 0.2 to about 1% w/v), polyvinyl alcohol (e.g., about 0.1 toabout 4% w/v), povidone (e.g., about 0.1 to about 2% w/v), zinc sulfate(e.g., about 0.25% w/v), anhydrous lanolin (e.g., about 1 to about 10%w/v), lanolin (e.g., about 1 to about 10% w/v), light mineral oil (e.g.,≦about 50% w/v), mineral oil (e.g., ≦about 50% w/v), paraffin (e.g.,≦about 5% w/v), petrolatum (e.g., ≦about 100% w/v), white ointment(e.g., ≦about 100% w/v), white petrolatum (e.g., ≦about 100% w/v), whitewax (e.g., ≦about 5% w/v), yellow wax (e.g., ≦about 5% w/v), ephedrinehydrochloride (e.g., about 0.123% w/v), naphazoline hydrochloride (e.g.,about 0.01 to about 0.03% w/v), phenylephrine hydrochloride (e.g., about0.08 to about 0.2% w/v), and tetrahydrozoline hydrochloride (e.g., about0.01 to about 0.05% w/v). In certain instances, percent amounts utilizedherein are percent amounts by weight.

In further embodiments, the therapeutically effective concentration ofhyaluronic acid or sodium hyaluronate is in the range of 10-100,000μg/mL, preferably 500-5,000 mg/mL, and the therapeutically effectiveconcentration of the surface active phospholipids is in the range of10-10,000 μg/mL, such surface active phospholipids include, but are notlimited to, L-α-dipalmitoylphosphatidylcholine (DPPC),phosphatidylcholine (PC), phosphatidylethanolamine (PE) andsphingomyelin (Sp), or other neutral and polar lipids.

The lubricating composition as disclosed herein may further comprisesone or more pharmaceutically acceptable carriers or vehicles comprisingany acceptable materials, and/or any one or more additives known in theart. As used herein, the term “carriers” or “vehicle” refer to carriermaterials suitable for topical drug administration. Carriers andvehicles useful herein include any such materials known in the art,which are nontoxic and do not interact with other components of thecomposition in a deleterious manner. Various additives, known to thoseskilled in the art, may be included in the composition. For example,solvents, including relatively small amounts of alcohol, may be used tosolubilize certain drug substances. Other optional additives includeopacifiers, antioxidants, fragrance, colorant, gelling agents,thickening agents, stabilizers, surfactants, and the like. Other agentsmay also be added, such as antimicrobial agents, to prevent spoilageupon storage, i.e., to inhibit growth of microbes such as yeasts andmolds. Suitable antimicrobial agents are typically selected from thegroup consisting of the methyl and propyl esters of p-hydroxybenzoicacid (i.e., methyl and propyl paraben), sodium benzoate, sorbic acid,imidurea, and combinations thereof. Permeation enhancers and/orirritation-mitigating additives may also be included in thepharmaceutical composition of the present invention.

In certain embodiments, the pharmaceutically acceptable carriercomprises a phosphate buffered saline or an osmotically balanced saltsolution of tear electrolytes, including one or more of sodium chloridein about 44% to about 54% mole fraction, potassium chloride in about 8%to about 14% mole fraction, sodium bicarbonate in about 8% to about 18%mole fraction, potassium bicarbonate in about 0% to about 4% molefraction, calcium chloride in about 0% to about 4% mole fraction,magnesium chloride in about 0% to about 4% mole fraction, trisodiumcitrate in about 0% to about 4% mole fraction, and hydrochloric acid inabout 0% to about 20% mole fraction or sodium hydroxide in about 0% toabout 20% mole fraction. In certain embodiments, the pharmaceuticalcarrier can be formulated to generate an aqueous electrolyte solution inabout 150-200 mM range. Other suitable formulations, such as ointments,creams, gels, pastes, and the like, suitable for topical administration,are also contemplated in the present invention. In certain embodiments,electrolytes provide proper osmotic balance when combined with PRG4 tomake a solution ophthalmically acceptable.

The present invention further provides a method for providing ocularboundary lubrication to an individual in need thereof comprisingapplying to an eye of the individual an ophthalmic device comprising anophthalmic lens with an outer surface and a inner surface and an ocularboundary lubricant composition disposed on at least a portion thereofone or more ocular boundary lubricant molecules selected from the groupconsisting of PRG4, a PGR4 inducer, hyaluronic acid, sodium hyaluronate,and a phospholipid, in an amount effective to provide ocular boundarylubrication in an individual wearing the ophthalmic lens. In oneembodiment, the invention method is used for treating ocular surfacehyperosmolarity in the individual who wear the ophthalmic lens. Theinvention method provides a sacrificial mechanism on the ophthalmic lensto mitigate shear stress, as discussed above.

Throughout this application, various publications are referenced. Thedisclosures of all of these publications and those references citedwithin those publications in their entireties are hereby incorporated byreference into this application in order to more fully describe thestate of the art to which this invention pertains.

It should also be understood that the foregoing relates to preferredembodiments of the present invention and that numerous changes may bemade therein without departing from the scope of the invention. Theinvention is further illustrated by the following examples, which arenot to be construed in any way as imposing limitations upon the scopethereof. On the contrary, it is to be clearly understood that resort maybe had to various other embodiments, modifications, and equivalentsthereof, which, after reading the description herein, may suggestthemselves to those skilled in the art without departing from the spiritof the present invention and/or the scope of the appended claims.

Other features and advantages of the invention will be apparent from thefollowing description of the preferred embodiments thereof and from theclaims. These and many other variations and embodiments of the inventionwill be apparent to one of skill in the art upon a review of theappended description and examples.

EXAMPLES Example 1 PRG4 mRNA Expression in Human Corneal andConjunctival Epithelial Cells

Human corneal epithelial cells were isolated from the corneoscleral rimsof male and female donors. Cells were processed either directly (n=8),or first cultured in phenol red-free keratinocyte serum free media(n=2). Bulbar conjunctivae (n=2), conjunctival impression cytologysamples (n=9), immortalized human conjunctival epithelial cells afterculture (n=1), NOD mouse lacrimal glands (n=5 adult mice/sex, 10glands/sample), and BALB/c mouse meibomian glands (n=7 adult mice/sex,glands from 28 lids/sample) were obtained during surgical procedures.These samples were processed for the analysis of PRG4 mRNA by usingprimarily RT-PCR (n=18 human, all mouse) and Affymetrix GeneChips (n=4human corneas). The PRG4 primers for PCR spanned over 1 kbp of intronsequences, in order to suppress amplification of contaminatingchromosomal DNA (Table 1). Amplified samples were screened for thepresence of PRG4 products by using agarose gel electrophoresis and anAgilent 2100 Bioanalyzer. To confirm the identity of amplicons, PCRproducts from cornea samples (n=2), conjunctival epithelial cells (n=1)and a human liver standard (n=1) were sequenced with a Genetic Analyzerat the Massachusetts Eye and Ear Infirmary DNA Sequencing Center forVision Research (Boston, Mass.) and resulting data were analyzed withBLASTn searches of GenBank databases.

TABLE 1Oligonucleotide primers designed for RT-PCR analysis of PRG4 mRNAAmplicon   Size Species Orientation Nucleotide sequence (5′-3′) Exons(bp) Human Sense GATGCAGGGTACCCCAAA (SEQ ID NO: 2) 9-12 526 AntisenseCAGACTTTGGATAAGGTCTGCC (SEQ ID NO: 3)

It was demonstrated that PRG4 mRNA is present in all human corneal andconjunctival epithelial cell and impression cytology samples. Theidentity of PRG4 PCR products was confirmed by DNA sequence analysis(Table 2). The results show that PRG4 is transcribed in human cornealand conjunctival epithelial cells.

TABLE 2 Identification of amplicon sequences from human cornea,conjunctival and liver samples Aligned Base Total Base Sequencing PairsTo Pairs from BLASTn Search Direction Human PRG4 Amplicon Identity HumanLiver Standard A Forward 495 500 Human PRG4 A Reverse 488 491 Human PRG4B Forward 496 499 Human PRG4 B Reverse 498 500 Human PRG4 Human Cornea(24 year old female) A Forward 497 499 Human PRG4 A Reverse 490 492Human PRG4 B Forward 500 504 Human PRG4 B Reverse 498 501 Human PRG4Human Cornea (51 year old female) A Forward 498 499 Human PRG4 A Reverse474 489 Human PRG4 B Forward 496 498 Human PRG4 B Reverse 490 491 HumanPRG4 Human Conjunctival Epithelial Cells A Forward 496 499 Human PRG4 AReverse 490 492 Human PRG4 B Forward 495 499 Human PRG4 B Reverse 474491 Human PRG4 Two different samples (A & B) of each preparation weresequenced in forward and reverse directions. The human cornea sampleswere epithelial cells from the corneoscleral rims of female donors. Thegene accession number for human PRG4 is NM_005807.

Example 2 Reduction of Friction In Vitro with the Addition of PRG4(Lubricin)

An in vitro friction test with clinically relevant interfaces, such asan ocular surface-eyelid and ocular surface-contact lens interface isdescribed below. Clinically relevant methods capable of quantitativelyassessing the lubricating ability of artificial tears are currentlylacking. Friction tests with synthetic (e.g. latex and glass) ornon-ocular ‘native’ surfaces (e.g. umbilical cord vein segments) mayfacilitate some, but likely not all of the molecular interactions thatoccur during articulation/blinking. Indeed, the relevance of dataobtained with non-tissue interfaces is unclear.

An annulus-on-disk rotational test configuration has been shown to beideal for studying boundary lubrication at an articularcartilage-cartilage interface. A boundary mode of lubrication isindicated by kinetic friction being invariant with factors thatinfluence formation of a fluid film, including sliding velocity andaxial load. This is because surface-to-surface contact is occurring, andsurface bound molecules contribute to lubrication (by decreasingfriction and wear). Boundary lubrication has been discovered to be acritical and operative mechanism at the ocular surface, like it is atthe articular cartilage surface. Therefore, the in vitro friction testpreviously developed and characterized to study boundary lubrication atan articular cartilage-cartilage interface was modified for the study ofocular surface-eye lid and ocular surface-contact lens interfaces.

To determine the test conditions in which boundary lubrication isdominant at the ocular surface-eyelid and ocular surface-contact lensinterfaces, the dependence of frictional properties on axial load andsliding velocity was examined. Normal fresh human ocular surfaces(resected corneas with ˜3 mm of sclera) were obtained from the Lions EyeBank of Alberta. The resected corneas were stored in Optisol-GS at 4° C.and used within 2 weeks. Eyelids (age 60-80 years old) were obtainedfrom the University of Calgary Body Donation Program within 1-3 daysafter death and used immediately or stored at −20° C. in saline for atmost 2 weeks until use. Comparative lubricants consisted of Lens PlusSterile Saline Solution (Advanced Medical Optics) as a negative control;Systane® Lubricant Eye props (Alcon Laboratories), Refresh TearsLubricant Eye props (Allergan), Aquify® Long Lasting Comfort props (CIBAVision) and Blink® Tears Lubricant Eye props (Advanced Medical Optics)as test lubricants.

The friction test schematic is shown in FIG. 6. The corneal ocularsurface (605) was fastened to the spherical end of an inertnon-permeable semi-rigid rubber plug cylinder (603) (radius r=6 mm) byapplying super glue to the sclera. This plug cylinder (603) was attachedto the rotational actuator of the mechanical testing machine (BoseELF3200) thus forming the bottom articular surface. An annulus (601) (outerradius=3.2 mm, inner radius=1.5 mm) was punched from the eyelid (604),and was attached to the linear actuator coupled with an axial load (N)and torsion (τ) load cell, thus forming the upper articulating surface.Lubricant bath 602 was formed by securing an inert tube around the plugcylinder (603).

Samples were first tested in saline, then in one of the three (3) testlubricants. The lubricant bath was filled with ˜0.3 ml, and thearticulating surfaces allowed to equilibrate with the lubricant. Thesample surfaces were slowly (0.05 mm/s) brought into contact andcompressed until the spherical plug flattened out and the entire annulareyelid surface was in contact with the cornea (605). The resultingnormal stress (calculated from axial load as, in units of MPa, asN/(π[r² _(outer)−r² _(inner)]) can be varied by using differentstiffness rubber plugs to mimic physiological stresses ˜5 kPa. The testsequence was initiated by preconditioning the sample by rotating +4revolutions (rev) and reset with −4 revolutions at a physiologicallyrelevant effective linear sliding velocity, veff=30 mm/s (whereveff=ωReff, ω is the angular frequency, and Reff=2.4 mm is the effectiveradius calculated by integrating the shear stress distribution over theannular contact area). Samples were then tested by rotating +4revolutions, immediately followed by −4 reset revolutions at veff=30,10, 1, 0.3 and then 30 mm/s, with a dwell time of 12 second between eachrevolution. The test sequence was then be repeated in the oppositedirection of rotation.

To evaluate the lubrication properties of the ocular surface, twofriction coefficients (μ) of the form μ=τ/(R_(eff)N)) where is torque,R_(eff) is effective radius, and N is axial load, described above. Astatic friction coefficient, which reflects the resistance to the onsetof motion, μ_(static) was calculated as the peak value of μ, just after(within)˜10° the start of rotation. An average kinetic frictioncoefficient, which reflects the resistance to steady state motion,<μ_(kinetic)> was calculated from p averaged during the third and fourthcomplete test revolution. Both μ_(static) and <μ_(kinetic)> wereaveraged for the + and − revolutions in each test to account forpotential directional effects on τ measurements. Data was collected at afrequency of 20 Hz.

The results of lubricin (PRG4) added to the corneal surface at aconcentration in the range of 100-300 ug/mL are shown in FIG. 7.Lubricin had a friction lowering effect at the eyelid interface, both interms of kinetic and static friction, at all velocities. At aconcentration 1/10th of that of physiological hyaluronic acid, lubricinwas similar to Blink® Tears Lubricant Eye props, which containshyaluronic acid. In combination, the two lubricants are better thaneither alone.

FIG. 8 demonstrates the reduction of in vitro cornea/lid kineticfriction measured during the first minute after the addition oflubricin, as compared to Aquify® eye drops. Lubricants were thoroughlywashed from the ocular surface using saline between tests. A synergisticeffect (reduced μ_(kinetic) over either alone) was evident when Aquify®(with hyaluronic acid) was combined with lubricin. The saline repeat waslower than the original saline control. This showed a retention oflubricin's effect even after washing with saline, suggesting that themolecules were binding to the ocular surface, and that lubricindemonstrated superior retention time as compared to sodium hyaluronatealone.

FIG. 9 demonstrates the reduction of in vitro cornea/lid kineticfriction measured during the 5th minute after the addition of lubricin,as compared to Aquify® eye drops. A synergistic effect (reducedμ_(kinetic) over either alone) was evident when Aquify® (with hyaluronicacid) was combined with lubricin. The friction coefficient of Aquify®had returned to statistical equivalence to saline after 5 minutes,whereas lubricin remains lower, as did the combination of lubricin andhyaluronic acid.

FIG. 10 shows the reduction of kinetic friction coefficient over time,following addition of lubricin. Again, the continual reduction suggestedbinding to the ocular surface.

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1. An ophthalmic device comprising an ophthalmic lens with an outersurface and an inner surface and a sacrificial mechanism disposed on atleast a portion of the outer or inner surface in an amount effective toprovide ocular boundary lubrication in an ocular environment of anindividual wearing the ophthalmic lens.
 2. The ophthalmic device ofclaim 1, wherein the sacrificial mechanism comprises a plurality ofsurface bound receptors.
 3. The ophthalmic device of claim 2, whereinthe surface bound receptors comprise surface bound PGR4.
 4. Theophthalmic device of claim 3, wherein the device further comprises alubricating composition associated with the surface bound PGR4.
 5. Theophthalmic device of claim 4, wherein the lubricating compositioncomprises a gel forming agent, a surfactant, or a combination thereof.6. The ophthalmic device of claim 5, wherein the lubricating compositioncomprises at least one gel forming agent, the at least one gel formingagent comprising an effective amount of hyaluronic acid, sodiumhyaluronate, or a combination thereof.
 7. The ophthalmic device of claim5, wherein the surfactant comprises an effective amount of one or moresurface active phospholipids.
 8. The ophthalmic device of claim 7,wherein the surfactant active phospholipid is selected from the groupconsisting of L-α-dipalmitoylphosphatidylcholine, phosphatidylcholine,phosphatidylethanolamine, and sphingomyelin.
 9. The ophthalmic device ofclaim 2, wherein the surface bound receptors comprise hyaluronic acid,and wherein the device further comprises a lubricating compositionreversibly associated with the hyaluronic acid, wherein the lubricatingcomposition is selected from the group consisting of a gel formingcomposition comprising PGR4 and a surfactant composition comprising oneor more surface active phospholipids.
 10. The ophthalmic device of claim9, wherein the surfactant active phospholipid is selected from the groupconsisting of L-α-dipalmitoylphosphatidylcholine, phosphatidylcholine,phosphatidylethanolamine, and sphingomyelin.
 11. The ophthalmic deviceof claim 2, wherein the surface bound receptors comprise DNA aptamers.12. The ophthalmic device of claim 1, effective to inhibit protein orlipid adsorption on the outer surface, inner surface, or both surfacesof the ophthalmic lens.
 13. The ophthalmic device of claim 3, whereinthe PRG4 has an average molar mass of between 50 kDa and 400 kDa, andcomprises recombinant PGR4, isolated naturally occurring PGR4, or afunctional fragment thereof.
 14. The ophthalmic device of claim 2,wherein the surface bound receptors are adhered to the ophthalmic lenssurface by direct adsorption, hydrophobic ionic, or covalent binding orby linker chemistries selected from the group consisting of homo- orhetero-bifunctional linkers, N-hydroxy succinimidyl esters, biotin,avidin, streptavidin, maleimide, thiol bonding, amines, hydrazones,dendrimers, and carbodiimides.
 15. The ophthalmic device of claim 5,wherein the lubricating composition further comprises one or moreophthalmically acceptable agents selected from the group consisting ofan ophthalmically acceptable demulcent, an ophthalmically acceptableexcipient, an ophthalmically acceptable astringent, an ophthalmicallyacceptable vasoconstrictor, an ophthalmically acceptable emollient, andtear electrolytes.
 16. An ophthalmic device comprising an ophthalmiclens with an outer surface and an inner surface and an ocular boundarylubricant composition disposed on at least a portion thereof one or moreocular boundary lubricant molecules selected from the group consistingof PRG4, a PGR4 inducer, hyaluronic acid, sodium hyaluronate, and one ormore phospholipids, in an amount effective to provide ocular boundarylubrication in an ocular environment of an individual wearing theophthalmic lens.
 17. A method for providing ocular boundary lubricationto an individual in need thereof who wears an ophthalmic lens,comprising applying to an eye of the individual an ophthalmic devicecomprising an ophthalmic lens with an outer surface and an inner surfaceand an ocular boundary lubricant composition disposed on at least aportion thereof one or more ocular boundary lubricant molecules selectedfrom the group consisting of PRG4, a PGR4 inducer, hyaluronic acid,sodium hyaluronate, and a phospholipid, in an amount effective toprovide ocular boundary lubrication in an ocular environment in theindividual.
 18. The method of claim 17, wherein the ophthalmic device isselected from any device of claims 1-15.
 19. The method of claim 18,wherein the individual is in need of treatment for ocular surfacehyperosmolarity.
 20. The method of claim 18, wherein the method providesa sacrificial mechanism on the ophthalmic lens to mitigate shear stress.21. An ophthalmic device comprising an ophthalmic lens with an outersurface and an inner surface; and PRG4, a PRG4 inducing compound, or acombination thereof associated with at least a portion of the outer orinner surface in an amount effective to provide ocular boundarylubrication in an ocular environment of an individual wearing theophthalmic lens.
 22. The ophthalmic device of claim 21, comprising PRG4bound to the surface of the ophthalmic lens.
 23. The ophthalmic deviceof claim 21, further comprising a lubricating composition disposed onthe surface of the ophthalmic lens, the lubricating compositioncomprising a gel-forming agent, a surfactant, or a combination thereof.